Monoclonal antibodies, or related products such as monoclonal antibodies conjugated with cytotoxic or cytolytic agents, have a number of therapeutic uses. For example, Monoclonal antibodies (or conjugates and related products) specific for the gp120 envelope protein of human immunodeficiency virus type 1 (HIV-1) can be used in therapy for AIDS or AIDS related complex (ARC), or in prophylactic treatment of seropositive but asymptomatic individuals, or uninfected individuals who have been exposed or are at a high risk of exposure to HIV-1. See U.S. application Ser. No. 07/343,540, filed Apr. 25, 1989. They can also be used to suppress or deplete B cells of a particular isotype for treatment of autoimmune diseases. In rheumatoid arthritis, for example, some autoantibodies of IgM or IgG, known as rheumatoid factors, are produced and bind to autologous IgG. The rheumatoid factors and IgG form immune complexes, which are believed to cause inflammation and tissue damage at the joints and other symptoms of rheumatoid arthritis. See U.S. patent application Ser. No. 07/408,123, filed Sep. 15, 1989. Suppression or depletion of malignant B cells with monoclonal antibodies (or mAb-conjugates) may also be desired in therapy for B cell lymphoma or leukemia. See U.S. application Ser. No. 07/531,787, filed Jun. 1, 1990. Suppressing or depleting the IgE expressing B cells with monoclonal antibodies (or mAb-conjugates) may also be an effective therapy for IgE-mediated allergies. See U.S. application Ser. No. 07/515,604, filed Apr. 27, 1990; published international application PCT/US88/04706.
One problem associated with in vivo administration of monoclonal antibodies and related products arises because monoclonal antibodies are generally animal-derived, and most often, mouse-derived. Murine antibodies are foreign proteins and often evoke an endogenous in vivo immune response which may reduce or destroy their therapeutic effectiveness. In addition, murine antibodies may cause an allergic or hypersensitivity reaction. In therapy, there is a need to readminister the antibody, and this re-administration increases the likelihood that these undesirable immune-related reactions will occur.
One way to ameliorate the problems associated with the in vivo use of a murine antibody is to convert the murine antibody to a "chimeric" antibody, consisting of the variable region of the animal or murine antibody joined to a human constant region. See, e.g., Morrison, S. L. et al. (1984) "Chimeric Human Antibody Molecules: Mouse Antigen-binding Domains with Human Constant Region Domains" Proc. Natl. Acad. Sci. USA 81: 6851; Neuberger, M. S. and Rabbits, T. H. "Production of Chimeric Antibodies" PCT Application No. PCT/GB85 00392; Sun, L. K. et al., (1987) Proc. Natl. Acad. Sci. USA 84:214; Liu, A. Y. et al., (1987) J. Immunol. 139: 3521; Sahagan, B. G. et al., (1986) J. Immunol. 137: 1066; Liu, A. Y. et al., (1987) Proc. Natl. Acad. Sci. USA 84: 3439. Because chimeric antibodies have a human constant region, and the constant region is the larger region which is believed to be primarily responsible for inducing immune or allergic responses against antibody, chimeric antibodies are less likely to evoke an undesirable immune-related response in humans. Nevertheless, an immune or allergic response against the murine variable region of the chimeric antibody or against the regions at the interface of the constant and variable regions can still result.
It is further noted that other animal or plant derived substances used in therapy or immunization, e.g., animal or plant derived toxins, hormones, and animal sera, are often highly immunogenic or allergenic. In addition, when a monoclonal antibody is conjugated to a toxin, the conjugate may be more immunogenic or allergenic than the toxin or mAb alone. Treatment with any of these agents may not be possible in certain individuals without suppressing the immune/allergic response.
Immunosuppressive agents, such as corticosteroid, cyclosporin, methotrexate, and cyclophosphamide, may be used to suppress such undesirable immune-related responses. However, they can produce serious side-effects. These side-effects result primarily because in addition to suppressing the humoral response, these non-specific agents also act against other immune system components and non-immune system cells.
The desirability of suppressing the immune response when foreign therapeutic proteins are administered has been recognized. See published International Application No. PCT/US89/02166. It has also been recognized that suppressing or depleting B cells by administering anti B-cell antibodies, or fragments or conjugates thereof, may be used in conjunction with administration of conventional mAbs, in order to suppress the undesirable immune responses against the conventional mAbs. See U.S. Pat. No. 4,861,579. However, this patent does not mention the suppression or elimination of B cells on an isotype-specific basis.